Design, Synthesis, and Evaluation of Allosteric Effectors for Hemoglobin

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Sickle cell disease (SCD) is an inherited blood disorder caused by a point mutation in hemoglobin (Hb), the protein in the red blood cell (RBC) responsible for the transport of oxygen (O 2 ) throughout the body. The mutation leads to the expression of sickle cell hemoglobin (HbS). Both Hb and HbS exist in equilibrium between oxygenated and deoxygenated forms; however, deoxygenated HbS can polymerize to form long fibers which distort the shape of RBCs into the characteristic sickled shape. The misshapen RBCs can obstruct blood vessels and capillaries, resulting in a vaso-occlusive crisis. Vaso-occulsion deprives tissues and organs of O 2 and can cause intense pain which often results in hospitalization. Chronic organ damage is a major cause of reduced life expectancy for SCD patients. Allosteric effectors are molecules which regulate protein function. HbS allosteric effectors can be used to decrease polymerization by stabilizing the oxygenated form of HbS, which leads to an increase in O 2 uptake and a decrease in the sickling of RBCs. Allosteric effectors that have been evaluated for the treatment of SCD include vanillin, 5-hydroxymethyl furfural (5-HMF), and voxelotor, which was approved by the U.S. Food and Drug Administration (FDA) for the treatment of SCD in 2019. 5-HMF did not progress to phase III clinical trials since it suffered from rapid metabolic degradation. However, several derivatives of 5-HMF and vanillin have been synthesized and evaluated as potential candidates for SCD treatment. Derivatives of these compounds have shown promise, but their shortcomings, such as high levels of oxidative metabolism, have prevented them from progressing into marketable drugs. Our efforts have produced multiple 5-HMF derivatives which have been evaluated for their potential to treat SCD. Each derivative was evaluated for its ability to increase O 2 affinity (i.e., P 50 , the partial pressure at which hemoglobin is 50% saturated with O 2 ). The synthesized aryl ether derivatives were evaluated, and results suggest that compounds with multiple aromatic aldehydes may have enhanced biological properties. One such derivative, compound 5, which features two furan aldehyde rings, exhibited increased O 2 continued...

Supramolecular cage-mediated cargo transport

“…Every living system is inseparable from the transport of substances. Blood circulates in organisms to transport substances to ensure normal life activities, 3 and the transport of many substances is dependent on carriers. Thus, the construction of artificial carriers for the transport of substances in different environments is of great significance for the separation of substances as well as the diagnosis and treatment of diseases.…”

“…1 Hemoglobin continuously transports oxygen into cells and transports carbon dioxide out of cells to maintain the normal life activities of the body. [2][3][4] The cell membrane contains various natural channel proteins; 5,6 thus, ions and biomolecules can pass in and out of the cells for material exchange to maintain equilibrium of the material inside and outside the cells. [7][8][9][10] In recent years, scientists have shown considerable interest in supramolecular cages with a wealth of sizes, shapes and photoelectric physical properties and possessing excellent applicability in recognition, [11][12][13] sensing, 14,15 catalysis, [16][17][18] biomedicine 19,20 and other important fields.…”